Barriers to medication adherence by caregivers of children with leukemia: an observational study

ABSTRACT Objective: To identify barriers to adherence to home oral maintenance chemotherapy in children with leukemia treated at a specialized cancer center. Methods: We used the Brief Medication Questionnaire (BMQ) as a tool for screening barriers to adherence. The level of adherence was calculated considering at least one positive response in each BMQ domain, defined as Regimen Screen, Belief Screen, and Recall Screen. A positive screening for belief barriers (PSB) indicates that the caregiver reports not understanding the medication's mechanism of action and adverse effects. Results: Three important barriers to adherence were identified: beliefs, number of children of the caregiver, and age of the caregiver. The primary caregivers included 32 mothers (80%), four fathers (10%), three grandmothers (7.5%), and one unrelated caregiver (2.5 %). Most caregivers with a PSB were mothers. A PSB indicates that the caregiver reports not understanding the medication's mechanism of action and adverse effects. Caregivers with two or more children (median, three) had more barriers to adherence. Caregivers with potential non-adherence tended to be older than those with potential adherence, although without statistical significance (p=0.079, Mann-Whitney U test). Conclusions: The main barriers to adherence to home oral maintenance chemotherapy in children with leukemia identified through interviews with their caregivers, most often mothers, were lack of understanding of the treatment regimen, a greater number of children, and older age.


INTRODUCTION
Childhood cancer is the leading cause of disease-related death, approximately 8%, in children and adolescents in Brazil.Recent data show that leukemia is the most commonly diagnosed malignancy affecting children and adolescents. 1Access to diagnosis of children with leukemia has increased significantly in the last 40 years, and cure rates of children treated in specialized centers reach 80% in high-income countries. 1eukemia is defined as a primary malignancy of hematopoietic stem cells.Because these cells are genetically altered in leukemia, they lose their differentiation ability while maintaining their proliferative capacity, with subsequent reduction in the production of healthy hematopoietic elements. 2Leukemia can be divided into subgroups based on the morphology of the affected cells and speed of disease progression, being classified as acute or chronic. 3They can be further divided into subgroups according to the type of affected cells, being characterized as lymphocytic leukemia, myeloid leukemia, and nonspecific or combined types. 3onventional leukemia treatment is divided into phases.The first phase aims to eliminate the pool of abnormal cells and is called remission induction.Once cytological remission has been achieved, less than 5% of bone marrow cells are expected to be leukemic with restoration of normal hematopoiesis. 4owever, despite no visible evidence of disease on cytology, studies have reported residual leukemia cells in the body, which requires further treatment to prevent relapse. 4The last phase is called maintenance, characterized by continuous treatment for several months. 4ultiple factors should be considered during treatment.Examples include the complexity of dosing regimens, the duration and cost of treatment, adverse events, subgroups with poor prognosis, a low health literacy population, cognitive and functional impairment, beliefs, concerns, patients' and caregivers' perceptions of health and treatment status, and lack of family and social support, among others. 5These factors may hinder treatment adherence, compromising clinical outcomes and potentially leading to relapse that might increase caregiving demands. 5arriers to adherence can be considered a public health problem because of consequences such as worsening of the disease, increased adverse events, and drug treatment failure, which may lead to disease progression and the need for hospitalization. 6he primary objective of this study was to identify barriers to adherence to home oral maintenance chemotherapy in children with leukemia treated at a specialized cancer center.

METHOD
The present study outlined the epidemiological profile of the main adherence barriers in children with leukemia treated at a referral hospital in Brasília, Brazil.We conducted a cross-sectional, observational, analytical study of 40 children diagnosed with leukemia between one and ten years of age who reached the maintenance phase of the chemotherapy protocol and were not hospitalized at the time of the study by convenience sample.
Data were collected through an interview with the person responsible for the child's treatment (caregiver) using the adapted version of the Brief Medication Questionnaire (BMQ) 7 translated into Portuguese and validated in Brazil as a tool for screening barriers to adherence.
A total of 49 children diagnosed with leukemia receiving maintenance chemotherapy were considered eligible for the study.Eight children were excluded from the study because they were older than ten years, and one child was excluded because the caregiver refused to complete the questionnaire.Therefore, the final sample consisted of 40 children.
Descriptive and association analyses were performed for levels of adherence and for levels of adherence by BMQ domain.The level of adherence was calculated considering at least one positive response in each BMQ domain, defined as Regimen Screen, Belief Screen, and Recall Screen.Responses to the questionnaire were categorized into levels of adherence according to the number of positive responses in any of the BMQ domains: high adherence (none), probable high adherence (1), probable low adherence (2), and low adherence (3 or more).A positive screening for belief barriers (PSB) indicates that the caregiver reports not understanding the medication's mechanism of action and adverse effects. 7ualitative variables characterizing the children and caregivers were expressed as frequency (n) and percentage (%) and associated using Pearson's chi-square test with continuity correction or Monte Carlo simulation if necessary (at least one cell was expected to have a value < 5).Quantitative variables were associated using the nonparametric Mann-Whitney U test and Kruskal-Wallis test for independent samples, considering these variables did not present normal distribution by the Kolmogorov-Smirnov test.Data were analyzed using IBM Statistical Package for the Social Sciences -SPSS, version 23, 2015.The significance level was set at 5% for all analyses.
The study followed the standards for research involving human subjects, set forth in Resolution 466/ 12
The responses to the BMQ questionnaire were associated with qualitative variables (Table 1) and quantitative variables (Table 2) to evaluate factors potentially associated with lower adherence to home oral maintenance chemotherapy among children.
Table 2 shows that only the variable 'number of children' was significantly associated with adherence to treatment by the caregiver.Caregivers with probable low adherence and low adherence had significantly more children than those with probable high adherence (Table 2 and Figure 1).
No qualitative sociodemographic variable of the caregivers was significantly associated with the Belief Screen in children with leukemia receiving home oral maintenance chemotherapy.The degree of kinship of the caregiver showed a strong tendency toward association with the Belief Screen, although without statistical significance (p=0.056,Pearson's chi-square test).Most caregivers with a PSB were mothers (Figure 2).
Figure 3 shows that caregivers with potential non-adherence tended to be older than those with potential adherence, although without statistical significance (p=0.079,Mann-Whitney U test).

DISCUSSION
Adherence barriers identified in the study were associated with beliefs, number of children, and drug regimen in relation to the age of the caregiver.In most cases, the primary caregiver was the mother (n=32, 80%).Mothers also reported a more PSB than did other caregivers.The results indicate the main areas that should be addressed by the multidisciplinary team to improve medication adherence. 7egarding the PSB, Bastos 8 conducted a qualitative study based on discourse analysis seeking to identify factors associated with anticipatory grief when caregivers, who most often are mothers, are told that their child has cancer or requires palliative care.The results showed that, while the mother is taking care of her child, she suffers from the belief that her child may die during treatment, leading to distress that may be related to the belief that the treatment is not working. 8 systematic review of health literacy, conducted at the University of Amsterdam in 2015, showed that people with low health literacy are less likely to understand health information.9 Our findings are consistent with these results, since there was a PSB regarding the understanding of the treatment regimen among the caregivers who had not completed elementary school (n=10, 25%).
Treating childhood cancer is complex.According to a quantitative analytical study conducted in 2019 in the oncology unit of a public hospital in Pernambuco, Brazil, patients with acute lymphoblastic leukemia are treated with several drugs, suggesting polypharmacy as the main factor leading to potential drug-drug interactions. 10This may be related to the PSB of mothers, which indicates they do not actually understand the mechanism of action of the simultaneous use of multiple drugs in the treatment regimen.
A qualitative study of ten women conducted in two phases from 2015 to 2018 using structured interviews, in addition to identifying that the mother was the primary caregiver of children with congenital syndrome (microcephaly associated with Zika virus infection), 11 also showed that mothers were overwhelmed by caring for their sick children, facing problems related to stress and responsibilities inherent in the treatment. 11,12enerally, mothers withdraw from their other children, leave their job and social life to dedicate themselves fully to the sick child, 13 and, as a consequence, they often experience mental health problems, high levels of stress, anxiety, and depression, decreased sense of well-being, and decreased quality of life. 14he number of children of the caregiver had a negative impact on adherence to treatment.Our study showed that caregivers with two or more children (median, three) had more barriers to adherence.A possible explanation for this association is that attention was not focused on the sick child, being shared between the sick sibling and healthy siblings. 15Another important issue to be addressed is that having a child with cancer changes the family dynamics, as there is a considerable impact on the spousal relationship and on the care of healthy siblings. 16The primary caregiver, usually the mother, feels guilty about the series of events that happen to the sick child, in addition to feeling that she is not fulfilling her responsibilities as a mother toward her other healthy children. 16 childhood cancer diagnosis can be considered a negative life event that interacts with aspects of personal life, environment, and family system, influencing the daily life of the entire family. 17he family daily routine often changes after a cancer diagnosis, which directly affects healthy siblings, who feel they are a burden on parents, and becomes an additional concern for parents, who     try to share the attention between all children. 16However, due to the severity of the disease, parental attention tends to be focused on the child with cancer, which may cause discomfort and psychological problems in the healthy siblings who also need care. 17][17] The present study also identified that, in the Regimen Screen, younger caregivers showed higher adherence to the prescribed leukemia treatment (age < 30 years; median, 29 years).It may be suggested that older people have habits, thoughts, and beliefs of their own that make it difficult to follow the physician's and multidisciplinary team's instructions about pill splitting, disposal, and administration as well as drug-drug and drug-food interactions, which are correctly performed by health professionals.Therefore, caregivers' difficulty following instructions becomes a barrier to adherence that worsens with advancing age.However, a study of six caregivers of older people conducted in Rio Grande do Sul, Brazil, showed that older caregivers were more resilient, that is, better able to adjust to change, which may facilitate adherence to treatment. 18his study has limitations.The method used considers polypharmacy a barrier to adherence.However, cancer treatment has multiple therapeutic targets, making monotherapy difficult.Another limitation is the questionnaire used, as the BMQ is not a standardized instrument to screen pediatric patients undergoing cancer treatment.The small number of caregivers interviewed can also be considered a limitation, in addition to the fact that the study was conducted in a single center.Therefore, further studies with a larger sample size are needed.Nevertheless, only a few patients were excluded from the study, and we were able to outline a profile of the pediatric population with leukemia treated at our institution and identify treatment-related factors that need to be addressed.Considering that the main barrier to adherence identified in this study was the understanding of the treatment regimen, additional studies are suggested to assess the level of patient satisfaction 19 in this population.
In this context, a descriptive cross-sectional study was conducted in a reference outpatient clinic in Brasília between 2017 and 2019 to evaluate the level of satisfaction of adolescents' caregivers with information received on the use of psychotropic drugs using the Satisfaction with Information about Medicines Scale (SIMS), and the results showed that most caregivers were dissatisfied with the information about treatment. 20Although we analyzed a different population in the present study, we ended up identifying the same problem of lack of caregiver understanding, especially of mothers (80%), as a barrier to adherence to treatment, thus highlighting the urgent need of additional studies to enhance caregiver understanding of leukemia treatment so that they can act as agents in the treatment of these children. 21other important factor to be evaluated in further studies is the follow-up that supports the use of event-free survival and overall survival in pediatric oncology after maintenance treatment of acute lymphocytic leukemia.
The main barriers to adherence to home oral maintenance chemotherapy in children with leukemia identified through interviews with their caregivers, most often mothers, were lack of understanding of the treatment regimen, a greater number of children, and older age.

Figure 1 .
Figure 1.Association between the number of children of the caregiver and adherence to home oral maintenance chemotherapy of children diagnosed with leukemia between 1 and 10 years of age treated at Hospital da Criança de Brasília José Alencar, Brazil.

Figure 2 .
Figure 2. Association between the degree of kinship of the caregiver and Belief Screen of adherence to home oral maintenance chemotherapy of children diagnosed with leukemia between 1 and 10 years of age treated at Hospital da Criança de Brasília José Alencar, Brazil.

Figure 3 .
Figure 3. Association between age of the caregiver and Regimen Screen of adherence to home oral maintenance chemotherapy of children diagnosed with leukemia between 1 and 10 years of age, treated at Hospital da Criança de Brasília José Alencar, Brazil.
of the Brazilian National Health Council, and was approved by the Research Ethics Committees of the University of Brasília School of Health Sciences (approval number 2.808.180;August 11, 2018) and Health Science Teaching and Research Foundation (Certificate of Presentation for Ethical Appreciation [CAAE] number 87652818.5.3001.5553and approval number 2.979.001;October 24, 2018).All caregivers provided written informed consent to be interviewed for the study.

Table 1 .
Descriptive analysis of sociodemographic variables of caregivers and children diagnosed with leukemia between 1 and 10 years of age in the maintenance phase of the chemotherapy protocol treated at Hospital da Criança de Brasília José Alencar, Brazil.
ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia.*Monthly income was reported as Brazilian minimum monthly salaries; the Brazilian minimum monthly salary (mms) denotes government regulation for a minimum monthly rate paid for a worker who works, on average, 44 hours a week for 4 weeks in a month.

Table 2 .
Association analysis between quantitative sociodemographic variables and adherence to home oral maintenance chemotherapy of children diagnosed with leukemia between 1 and 10 years of age in the maintenance phase of the chemotherapy protocol treated at Hospital da Criança de Brasília José Alencar, Brazil.